Multiple myeloma is a B cell malignancy characterized by the latent accumulation in bone marrow of secretory plasma cells with a low proliferative index and an extended life span. The disease ultimately attacks bones and bone marrow, resulting in multiple tumors and lesions throughout the skeletal system.
Approximately 1% of all cancers, and slightly more than 10% of all hematologic malignancies, can be attributed to multiple myeloma (MM). Incidence of MM increases in the aging population, with the median age at time of diagnosis being about 61 years. Currently available therapies for multiple myeloma include chemotherapy, such as vincristine, BCNU, melphalan, cyclophosphamide, adriamycin, and prednisone or dexamethasone, stem cell transplantation, Thalomid® (thalidomide), Velcade® (bortezomib), Aredia® (pamidronate), and Zometa® (zoledronic acid). Current treatment protocols, which include a combination of chemotherapeutic agents, yield a complete remission rate of only about 5%, and median survival is approximately 36-48 months from the time of diagnosis. Recent advances using high dose chemotherapy followed by autologous bone marrow or peripheral blood mononuclear cell transplantation have increased the complete remission rate and remission duration. Yet overall survival has only been slightly prolonged, and no evidence for a cure has been obtained. Ultimately, MM patients often relapse, even under maintenance therapy with interferon-alpha (IFN-α) alone or in combination with steroids.
CD38 is an example of an antigen expressed on such malignant plasma cells. Functions ascribed to CD38 include both receptor mediation in adhesion and signaling events and (ecto-) enzymatic activity. As an ectoenzyme, CD38 uses NAD+ as substrate for the formation of cyclic ADP-ribose (cADPR) and ADPR, but also of nicotinamide and nicotinic acid-adenine dinucleotide phosphate (NAADP). cADPR and NAADP have been shown to act as second messengers for Ca2+ mobilization. By converting NAD+ to cADPR, CD38 regulates the extracellular NAD+ concentration and hence cell survival by modulation of NAD-induced cell death (NCID). In addition to signaling via Ca2+, CD38 signaling occurs via cross-talk with antigen-receptor complexes on T and B cells or other types of receptor complexes, e.g. MHC molecules, and is in this way involved in several cellular responses, but also in switching and secretion of IgG.
Today various approaches to target CD38 are disclosed in the art. For example antibodies specific for CD38 are described in WO1999/62526 (Mayo Foundation); WO200206347 (Crucell Holland); US2002164788 (Jonathan Ellis) which is incorporated by reference in its entirety; WO2005/103083, U.S. Ser. No. 10/588,568, which is incorporated by reference in its entirety, WO2006/125640, U.S. Ser. No. 11/920,830, which is incorporated by reference in its entirety, and WO2007/042309, U.S. Ser. No. 12/089,806, which is incorporated by reference in its entirety (MorphoSys AG); WO2006099875, U.S. Ser. No. 11/886,932, which is incorporated by reference in its entirety (Genmab); and WO08/047242, U.S. Ser. No. 12/441,466, which is incorporated by reference in its entirety (Sanofi-Aventis). However, in order to improve efficacy of CD38 antibodies, different combination therapies of antibodies specific for CD38 and other agents are already disclosed e.g. in WO200040265, U.S. Ser. No. 09/226,895, which is incorporated by reference in its entirety, (Research Development Foundation); WO2006099875 and WO2008037257, U.S. Ser. Nos. 11/886,932 and 12/442,808, which is incorporated by reference in its entirety, (Genmab); WO2012/041800 (MorphoSys AG) and WO2010061360, U.S. Ser. No. 13/131,389, which is incorporated by reference in its entirety, WO2010061359, U.S. Ser. No. 13/130,867, which is incorporated by reference in its entirety, WO2010061358, U.S. Ser. No. 13/130,865, which is incorporated by reference in its entirety, and WO2010061357, U.S. Ser. No. 13/130,862, which is incorporated by reference in its entirety, (Sanofi Aventis), which are all incorporated by reference in their entireties.
However many forms of cancer involving CD38-expressing tumors still have a poor prognosis and present therapies are not sufficient. Thus, there is a need for improved methods for treating such forms of cancer.